ApoE gene and Alzheimer's disease (3)

In fact, the E4 variation of ApoE gene is a primitive alle, that is to say, the ApoE gene of our ancient ancestors is E4 / E4 There is still the highest proportion of E4 variants among Africans, with E4 carriers (E3 / E4 and E4 / E4) reaching 50-60% of the population in some regions of Africa With the evolution of human beings, especially after going out of Africa, E4 gradually disappeared As a new mutation, E3 seems to have more advantages in survival, replacing E4 as the main APOE genotype The E2 mutation occurred after the E3 mutation In the general population, about 60-70% of the population is E3 / E3 genotype, 20-25% of the population is E3 / E4, 10-15% of the population is E2 / E3, while homozygous E4 / E4 and E2 / E2 genotype are rare in the population The authors speculate that E4 may be more suitable for survival and reproduction in the environment of cholesterol depletion We have known that apoE4 has a strong binding ability with its receptor, which enables more cholesterol to be transported into cells, including germ cells Cholesterol is the precursor of synthetic sex hormones Therefore, individuals carrying E4 should have a strong reproductive advantage in the environment of lacking cholesterol in meat food However, the risk of cardiovascular disease and Alzheimer's disease related to E4 are all post reproductive diseases, so it is unlikely to change the selection advantage The most likely reason for E3 to replace E4 is that after leaving Africa, E4 carriers are more likely to be infected with a disease and die At the same time, in the new food environment, such as abundant cholesterol rich food, the E3 population can have the same or better reproductive advantages as the E4 population, so that the descendants carrying E3 have more reproductive opportunities However, E2 mutation is following E3 mutation, which may be related to the abundance of high cholesterol food E4 is the highest in Africa and the lowest in Asia, while E2 is the highest in Asia Vietnamese and Thai are the highest in E2 My personal guess is that the abundant fish, shrimp, waterfowl and other foods in Yucun provide abundant cholesterol In such an environment, although the binding ability of apoe2 and its receptor in E2 population is greatly reduced, there is still enough food source cholesterol for reproductive cells to synthesize sex hormone E2 carriers have no reproductive disadvantage in such an environment, but other intelligent advantages may be enhanced It has the advantage of overall reproduction Although a small number of E2 / E2 homozygous carriers will suffer from type III hyperlipidemia, those with one E2 variant have lower blood cholesterol, are less likely to suffer from Alzheimer's disease and cardiovascular disease, and have a longer life span As we mentioned earlier, more than 95% of Alzheimer's disease is a polygenic complex disease, that is to say, multiple genes participate in the pathogenesis, and gene factors and living environment factors interact to determine the age and course of disease There are nearly 100 genes related to the risk of Alzheimer's disease, the pathogenesis is really clear, and the effect amount is significantly concentrated in 20 genes These genes are mainly responsible for four biological channels Amyloid production channel: app, PSEN1, psen2, adam2, BACE1, Bin1, CD2AP; amyloid clearance channel: apoE, ABCA1, ABCA7, clu, IDE, LRP1, LRP2, picalm, SORL1; immune and neuroinflammatory response channel: CD33, plau, TREM2, treml2, tyrobp; nerve growth and repair channel: unc5c, EphA1; tau protein channel: MAPT It is not difficult to see that the production and clearance of amyloid are the two most important pathogenic channels, and the number of genes involved is the largest Then there's the neuroinflammatory response pathway, nerve repair and other pathways Whether everyone will suffer from senile dementia in his or her lifetime depends on gene and environmental factors In front of genes, everyone is never equal Some people are born with good genes, while others are born with poor genes If we can change the environmental factors, such as diet, nutrition and living habits, we may be able to effectively reduce the risk of genes Figure 9: pathological pathways associated with Alzheimer's disease Gene detection will be the most effective early warning test for Alzheimer's disease Unlike cardiovascular disease and other metabolic diseases, Alzheimer's disease has no diagnosis before its onset, but once it is diagnosed, it is too late, and there is no treatment for reversal and remission Moreover, the pathological process of Alzheimer's disease has occurred in the brain 15-20 years before the occurrence of cognitive and memory symptoms This pathological process leads to the gradual death of nerve cells, and the dead nerve cells are irrecoverable and irreplaceable When the number of dead nerve cells exceeds a certain amount, cognitive and memory disorders will become obvious, and the current diagnosis method can be confirmed If you want to reduce and slow down the damage of nerve cells, especially for the high-risk population, you need to prevent 15-20 years in advance In the absence of symptoms, how to prevent, what kind of prevention methods are the most targeted and effective, and future gene detection may provide the best guidance Gene testing can not only predict disease risk at a very young age, but also accurately tell those biological channels through what kind of mechanism to increase risk Correspondingly, we need targeted prevention and treatment measures Unfortunately, although we have known that E4 mutation of ApoE gene is the most important gene risk, so far, there is no prevention and treatment measures for E4 mutation The Company GB healthwatch, where the author works, is working to develop and validate preventive measures that pass the genetic nutrition mechanism The evidence for the amyloid hypothesis in Alzheimer's is still robust, but why are none of the drugs developed based on this hypothesis successful in clinical trials? Here the author makes some bold conjectures First, amyloid accumulation is a major cause of Alzheimer's disease, but amyloid itself does not directly lead to the clinical symptoms of Alzheimer's disease, leading to the progressive death of brain nerve cells Amyloid accumulation is a necessary but not sufficient condition The accumulation of amyloid protein either blocks the nutritional supply of nerve cells or causes physical damage to nerve cells More likely, the accumulation of amyloid protein triggers the inflammatory immune system in the brain at a certain time Once triggered, the immune cells kill the cells around the powdery egg plaque and damage the nerve cells continuously Therefore, for the triggered Alzheimer's disease, no matter in the early or late stage, it is impossible to alleviate the symptoms or the remission process by clearing the amyloid plaque itself The treatment that can control the process must be able to effectively inhibit the continued phagocytosis of immune cells on nerve cells It's like long-term exposure to high cholesterol is the main cause of myocardial infarction, but when myocardial infarction occurs, the use of cholesterol lowering drugs can not improve myocardial infarction, but requires thrombus and stent to improve symptoms Second, there are two main types of drugs based on amyloid, one is to inhibit the production of a β, the other is to increase the clearance of a β Because a β is an inevitable product of nerve cell activity, inhibition of a β production inhibits nerve activity The former two drugs not only do not improve symptoms, but also make symptoms worse faster The increase of a β clearance is mainly due to antibody drugs, which can reduce a β plaques in the brain of patients, but does not improve the cognition of patients On the day of release, Biogen is going to submit the listing application of aducanumab to FDA This antibody drug is based on the mechanism of eliminating amyloid protein A few months ago, it was announced that the clinical experiment failed The development of the drug based on the hypothesis of amyloid protein is almost a devastating blow However, the reanalysis of clinical experimental data shows that the cognitive decline of some patients is slowed down in the high dose group of early and middle stage patients This may give the amyloid hypothesis confidence again It should be said that a β clearance is a desirable pathway, but it needs to start 15-20 years before symptoms appear Just like taking cholesterol lowering drugs to reduce the risk of cardiovascular disease, most of them are taken from the age of 40-50 For the family hypercholesterolemia (FH) population with high risk, cholesterol lowering drugs need to be taken from the age of 20, which can delay the occurrence of myocardial infarction for 10-15 years Third, the use of antibody drugs to directly remove a β is too simple and crude and too expensive to be used for long-term and mass preventive treatment We need more clever drug design, and it's better to use channels that already exist in the body to reduce a β deposition Fourth, we can't imagine the emergence of a single magic drug We need targeted combination drugs in different stages of the course of the disease It is still to take the prevention and treatment of familial hypercholesterolemia (FH) and cardiovascular disease as a reference to carry out gene evaluation for high-risk population If the main pathogenic channel comes from amyloid deposition, the preventive treatment to reduce amyloid deposition should start as early as possible Prophylactic treatment has a high demand for drugs Absolute safety and low price are both necessary Unfortunately, few pharmaceutical companies are willing to do this Maybe molecular nutrition products can take on this task As mentioned before, the synthesis and transport of cholesterol in the brain are closely related to the formation and clearance of amyloid plaques, and the related signal channels are regulated by nutrients In addition, on the basis of reducing the deposition of amyloid protein, drugs that inhibit the immune killing and promote the self-healing of nerve cells in the brain may be more effective in inhibiting and alleviating the course of disease However, to reverse the course of disease is almost impossible, we should not have illusions about such a magic medicine In addition to the repeated failures of drugs based on the amyloid hypothesis, the clinical verification based on other hypotheses also makes many ideals disillusioned For example, the combination of antioxidant treatment, not only can not reduce the symptoms of memory and cognitive impairment, but also make the disease develop faster Moreover, the use of high-dose B group vitamin treatment can not reduce symptoms, but increase the number of anxiety and depression So far, only gv-971 of China Green Valley pharmaceutical has been reported to be able to slow down the symptoms and progress of Alzheimer's disease Gv-971 is a polysaccharide extracted from seaweed, and its mechanism is not clear According to the results of the mouse experiment, it is suggested that the change of the activity of immune cells infiltrated into the brain may be through the change of intestinal flora, and the slow down of the symptoms and process of Alzheimer's disease by reducing the inflammatory response of the brain It is suggested that inhibition of brain inflammatory response is a feasible treatment for Alzheimer's disease However, the results of gv-971 phase III clinical trial have not been published in the international journal It is hoped that more independent clinical institutions will participate in confirming the therapeutic effect of gv-971 Let's wait and see reference: Aisen PS, Schneider LS, Sano M, et al High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial JAMA 2008 Oct 15;300(15):1774-83 PMID: 18854539 Galasko DR, Peskind E, Clark CM, et al Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures Arch Neurol 2012 Jul;69(7):836-41 PMID: 22431837.